tbuckley/cabot-search huggingface dataset:
P480: DNMT AND HDAC INHIBITION INDUCES IMMUNOGENIC NEOANTIGENS FROM HUMAN ENDOGENOUS RETROVIRAL ELEMENT-DERIVED TRANSCRIPTS
Authors: Ashish Goyal, Jens Bauer, Joschka Hey, Dimitris Papageorgiou, Ekaterina Stepanova, Michael Daskalakis, Marissa Dubbelaar, Boris Klimovich, Melanie Maerklin, Malte Roerden, Oliver Muecke, Hans-Georg Rammensee, Fabricio Loayza-Puch, Jeroen Krijgsveld, Michael Lübbert, Juliane Walz, Christoph Plass
Journal: HemaSphere (2023)

Background: Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the resulting transcripts. These ERV-derived transcripts can splice into protein-coding exons and encode for chimeric open reading frames (ORFs) that were hypothesized to encode for putative neoantigens. However, the existence of these neoantigens has never been demonstrated experimentally. Aims: To test the hypothesis that treatment with DNA methyl transferase inhibitor (DNMTi) or histone deacetylase inhibitor (HDACi) can lead to the induction of neoantigens encoded in ERV-derived transcripts. Methods: RNA sequencing (RNA-seq), Ribosomal profiling (Ribo-seq), whole cell proteomics, Immunopeptidomics, Artificial antigen-presenting cells (aAPCs)-based induction of neoantigens specific CD8+ T cells, T cell cytotoxicity assay, and Enzyme-linked immunosorbent spot (ELISpot) assay. Results: We used RNA-seq from cancer cell lines treated with DNMTi and/or HDACi to assemble a de novo transcriptome and identified ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs) coding for novel open reading frames. Using immunopeptidomics, we further demonstrate the human leukocyte antigen (HLA) presentation of treatment-induced neopeptides (t-neopeptides) derived from novel ORFs encoded by TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response and cancer cell killing. The presence of t- neopeptides was further verified in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Summary/Conclusion: ERV-derived double-stranded RNAs contribute to the anti-neoplastic activities of epigenetic inhibitors like Decitabine, through the induction of viral mimicry. This study describes a novel category of ERV-derived immunogenic neopeptides, specifically induced upon epigenetic therapy that could serve as prime targets for novel combinatorial immunotherapeutic approaches in cancer patients. Keywords: Acute myeloid leukemia, decitabine, Cancer immunotherapy, Antigen presentation
S280: INDIVIDUALS WITH HFE C282Y HOMOZYGOSITY AND DIABETES HAVE ALMOST TWO-FOLD RISK OF DEATH COMPARED TO NON-CARRIERS WITH DIABETES: A PROSPECTIVE STUDY OF A 132,542-INDIVIDUAL GENERAL POPULATION COHORT
Authors: Mathis Mottelson, Jens Helby, Børge Grønne Nordestgaard, Christina Ellervik, Thomas Mandrup-Poulsen, Jesper Petersen, Stig Egil Bojesen, Andreas Glenthøj
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Homozygosity for the HFE C282Y variant causes hereditary haemochromatosis, potentially leading to diabetes, liver disease, and heart disease. Aims: We tested whether C282Y homozygosity increased risk of diabetes, liver disease, and heart disease even in individuals with normal plasma iron, transferrin saturation, or ferritin. Further, we tested whether C282Y homozygotes with diabetes, liver disease, or heart disease had increased risk of death compared to non-carriers with these diseases. Methods: We genotyped 132,542 consecutive individuals in a general population cohort for the HFE C282Y variant and found 422 homozygotes. Individuals were followed prospectively for up to 27 years. Information on hospital contacts was from the National Patient Register, covering all Danish hospitals. Results: During follow-up 17,688 individuals died from any cause while 7,702, 2,804, and 21,769 individuals had a hospital contact with diabetes, liver disease, or heart disease, respectively. When comparing C282Y homozygotes to non-carriers, hazard ratios were 1.66 (95% CI:1.20-2.31;P=0.002) for diabetes, 2.16 (1.36-3.43;P=0.001) for liver disease, and 0.98 (0.75-1.27;P=0.86) for heart disease. Risk of diabetes was increased even in C282Y homozygotes with normal iron (hazard ratio 1.67;95% CI:1.15-2.42), transferrin saturation (2.49;1.41-4.39), or ferritin (4.35;1.81-10.48). C282Y homozygotes with diabetes had a hazard ratio for death from any cause of 1.94 (1.19-3.18;P=0.008) when compared to non-carriers with diabetes. The percentage of all deaths among C282Y homozygotes that could theoretically be prevented if a single disease was eliminated (the population attributable fraction) was 27.3% (12.4-39.7%) for diabetes and 14.4% (3.1-24.3%) for liver disease. Summary/Conclusion: Haemochromatosis C282Y homozygotes had increased risk of diabetes even when having normal levels of iron, transferrin saturation, or ferritin. Further, C282Y homozygotes with diabetes had an almost two-fold risk of death compared to non-carriers with diabetes. Current haemochromatosis treatment strategy centralized around lowering ferritin may inadequately reduce risk of diabetes and risk of death related to diabetes. Keywords: Causes of death, Iron metabolism, Mortality, Hemochromatosis
P346: DECIPHER STRUCTURAL ABERRATIONS OF THE PAX5 GENE AND THEIR CORRELATION WITH DIAGNOSTIC CLASSIFICATION AND TREATMENT OUTCOME IN B CELL LYMPHOBLASTIC LEUKEMIA
Authors: Tong Wang, Ming Liu, Panxiang Cao, Jiancheng Fang, Huanhuan LI, Jiaqi Chen, Hongxing Liu
Journal: HemaSphere (2023)

Background:PAX5 is an essential transcription factor required for B cell differentiation. It is known that PAX5 aberrations confer the occurrence of B cell lymphoblastic leukemia (B-ALL) in various forms of abnormality. However, due to the complexity of the structural variation of PAX5, comprehensive examination and analysis remain challenging. Aims: To decipher the structural aberrations of the PAX5 gene to investigate their correlation with diagnostic classification and treatment outcome in B-ALL. Methods: Optical genome mapping (OGM) and transcriptome sequencing (RNA-seq) were performed on the bone marrow samples of 21 newly diagnosed or relapsed/refractory B-ALL cases to decipher PAX5 structure variations including the formation of fusion genes, exon deletion, and exon duplication. Other pathological fusion genes and gene mutations in B-ALL were also analyzed, and patients were followed up for treatment outcomes. Results: A total of 11 of 21 cases (52.4%) were detected with PAX5 structural variations, including 5 children (age < 14 years) and 6 adults (2.5 ~ 55 years, median = 20), with a male: female = 4.5:1 (9/2). Of them, 5 cases (45.4%) carried PAX5 in-frame fusion genes, and the partner genes RNF38, BCL2, and NSD1 have not been reported. Four cases (36.3%) carried the concatenation of PAX5::ZCCHC7 fusion transcript due to 510Kb 9p focal deletion, which functionally resulted in the truncation of PAX5. The other 2 cases (18.3%) carried PAX5 focal deletions (exon6, exon6-7, respectively). IKZF1 alterations were observed in 8 of the 11 (72.7%) cases, with IK10 being the most common (4 cases). Eight of the 11 cases carried other genetic abnormalities that define B-ALL subtypes, including 2 BCR::ABL1, 3 BCR::ABL1-like (NUP214::ABL1, EBF1::PDGFRB, and RCSD1::ABL2, respectively), one E2A::PBX1, one ETV6::RUNX1, and one hyperdiploid case. Two cases were positive for [email protected], but without genetic abnormalities that define B-ALL subtypes. Six cases evaluated as high-risk received chimeric antigen receptor T cell (CAR-T) treatment, 5 of which were bridged to allogeneic hematopoietic stem cell transplantation (all0-HSCT), and these 5 cases maintained remission until the last follow-up (21-63m). The patient who was not bridged to allo-HSCT died of relapse 13 months after the disease onset. Summary/Conclusion:PAX5 structural aberrations are common and important genetic events in B-ALL with various forms, including in-frame gene fusions, 3’ deletion (PAX5::ZCCHC7), and focal exon deletions. OGM combined with RNA-seq helps to decipher pathological PAX5 structural abnormalities. PAX5 structural abnormalities mostly occur in BCR::ABL1-positive and BCR::ABL1-like patients and are often associated with IK10. CART bridging allo-HSCT therapy helps improve these patients’ prognosis and survival rates.Keywords: Acute lymphoblastic leukemia, PAX5
PB1715: UNLEASHING NATURAL KILLER (NK) CELLS TO PROMOTE ANTI-LEUKEMIC IMMUNITY
Authors: Ioanna Tsoukala, Alexander Schäffer, Irene Tirado-Gonzalez, Jasmin Röder, Jordi Pfeifer Serrahima, Mohammed H. Mosa, Devona Seotopo, Arnaud Descot, Winfried S. Wels, Hind Medyouf
Journal: HemaSphere (2023)

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Acute leukemias are a group of disseminated blood cancers that remain the leading cause of cancer-related death in children, and a major clinical challenge in adult and elderly patients. Similar to solid tumors, leukemic blasts actively convert their surrounding bone marrow microenvironment into a supportive niche that reinforces leukemic growth, promotes therapy resistance and facilitates immune evasion. Understanding the cellular and molecular mechanisms by which leukemic cells actively drive immune evasion is indispensable for the improvement of the current therapeutic arsenal. Natural killer (NK) cells are the cytotoxic arm of the innate immune system able to recognize and rapidly eliminate malignant cells without prior sensitization, by integrating stimuli from activating/inhibitory receptors, adhesion molecules and cytokines. Aims: Here, we aim to unveil the impact of the leukemia-associated microenvironment on NK function, the mechanisms leading to their dysfunction as well as potential means of therapeutic exploitation. Methods: To address our hypothesis various genetic, syngeneic models of acute leukemia as well as state-of-the-art techniques including spectral cytometry are employed. Results: We demonstrate that leukemic blasts impair the function of NK cells directly via cell-cell contact leading to downregulation of the major NK activating receptor NKG2D, as well as indirectly by imposing a suppressive tumor immune microenvironment. Notably, we provide proof-of-concept data demonstrating that restoration of NK cell function, directly by expression of an NKG2D-CAR construct, or indirectly by rewiring the suppressive microenvironment, elicits a potent NK-dependent anti-leukemic response, thereby re-establishing anti-leukemic immunity. Summary/Conclusion: Taken together, our data point to a key role of NK cells in hematological malignancies and highlight new avenues for therapeutic exploitation of these innate effectors. Keywords: Natural killer, Microenvironment, Acute leukemia, Immunotherapy
Disparities in cannabis use and documentation in electronic health records among children and young adults
Authors: Nazgol Tavabi, Marium Raza, Mallika Singh, Shahriar Golchin, Harsev Singh, Grant D. Hogue, Ata M. Kiapour
Journal: npj Digital Medicine (2023)

The legalizations of medical and recreational cannabis have generated a great deal of interest in studying the health impacts of cannabis products. Despite increases in cannabis use, its documentation during clinical visits is not yet mainstream. This lack of information hampers efforts to study cannabis's effects on health outcomes. A clear and in-depth understanding of current trends in cannabis use documentation is necessary to develop proper guidelines to screen and document cannabis use. Here we have developed and used a natural language processing pipeline to evaluate the trends and disparities in cannabis documentation. The pipeline includes a screening step to identify clinical notes with cannabis use documentation which is then fed into a BERT-based classifier to confirm positive use. This pipeline is applied to more than 23 million notes from a large cohort of 370,087 patients seen in a high-volume multi-site pediatric and young adult clinic over a period of 21 years. Our findings show a very low but growing rate of cannabis use documentation (<2%) in electronic health records with significant demographic and socioeconomic disparities in both documentation and positive use, which requires further attention.
P541: REAL-WORLD USE OF VENETOCLAX (VEN) IN PATIENTS (PTS) WITH ACUTE MYELOID LEUKEMIA (AML) IN A US REAL-WORLD EVIDENCE DATABASE (COTA)
Authors: Amer M. Zeidan, Leyla Hernandez- Donoso, Sejla Hodzic, Henry Owusu, Dhrubajyoti Pathak, Summera Zhou, Eytan Stein
Journal: HemaSphere (2023)

Background: VEN + hypomethylating agents (HMAs)/low-dose cytarabine was approved for the treatment of pts with AML who are ≥75 y or ineligible for intensive chemotherapy in 11/2018. Aims: To understand the real-world use, safety, and efficacy of VEN in the US clinical practice. Methods: This is a retrospective, descriptive analysis of deidentified secondary data from the COTA AML database, which included pt-level curated electronic health record data from centers across the US. Data were abstracted for adults diagnosed with AML who initiated first-line (1L) treatment on or after 01/01/2018 and received ≥1 VEN treatment at any point. Pts with no diagnosis date or with concurrent primary malignancies were excluded. Follow-up was until the last recorded event (last visit or death). The study period for this analysis was 01/2018 to 09/2022. Results: Of 3836 pts with AML in the database, 1163 pts initiated 1L treatment in or after 2018; of these, 636 received ≥1 VEN treatment at any point. See Table for baseline demographic data. Most VEN-treated pts were seen by community healthcare providers (407/636, 64%). Genetic/molecular data were limited. Of the most frequently tested mutations, the most common were TP53 (129/461, 28%), RUNX1 (109/444, 25%), TET2 (101/414, 24%), ASLX1 (92/417, 22%), and DNMT3A (91/424, 22%). Of pts who received VEN, 47% (299/636) received 1L VEN, and the majority (269/636, 42%) received VEN + HMAs. For pts with treatment prior to VEN (pretreated), 262/337 (78%) were previously treated with chemotherapy. 1L pts were more often treated in community centers than pretreated pts (73% vs 56%), had more comorbidities (56% vs 40%), and TP53 positivity (19% vs 10%) at baseline. Of 284 VEN-treated pts with available response data, 180 (63%) had a complete response (CR). Median OS (mOS) of VEN-treated pts was 14.4 mo from 1L treatment initiation (de novo AML, 17 mo; secondary AML, 14 mo). mOS from diagnosis was 14 mo for newly diagnosed and 18 mo for pretreated pts. Toxicity was the main cause of dose reduction and discontinuation. Median duration of VEN treatment was 78 d. Dose reduction was reported in ~30% of VEN-treated pts. Of VEN-treated pts, 53% (338/636) discontinued at least 1 VEN regimen, with a median time to discontinuation of 49.5 d. Summary/Conclusion: This study provides an overview of the real-world use of VEN in pts with AML in the US since its approval in 11/2018. Despite the study period starting earlier than VEN approval, almost half of pts with AML who initiated treatment after 2018 received 1L VEN. The real-world CR rate in VEN-treated pts with available data was 63%, but over half of VEN-treated pts had VEN treatment discontinuation.Keywords: AML, Venetoclax, Real world data
P713: EXPLORING CLONAL COMPETITION THROUGH 12-YEAR FOLLOW-UP OF AN MDS-RS PATIENT WITH DUAL SF3B1 MUTATIONS
Authors: Pedro Moura, Isabel Hofman, Yasuhito Nannya, Affaf Aliouat, Teresa Mortera-Blanco, Tetsuichi Yoshizato, Ryunosuke Saiki, Masahiro Nakagawa, Ann-Charlotte Björklund, Gunilla Walldin, Indira Barbosa, Monika Jansson, Francesca Grasso, Maria Creignou, Edda Elvarsdottir, Petter Woll, Sten Eirik Jacobsen, Seishi Ogawa, Eva Hellström Lindberg
Journal: HemaSphere (2023)

Background: Hematopoietic SF3B1 mutations are well-established as a driver event of clonal establishment and expansion in myelodysplastic syndromes with ring sideroblasts (MDS-RS). However, the mechanisms underlying the fitness advantage that allows SF3B1-mutant (SF3B1mt) hematopoietic stem and progenitor cells (HSPCs) to thrive remain poorly understood. Aims: Here we aim to unravel the molecular mechanisms of hematopoietic clonal competition through long-term longitudinal analysis of a dual SF3B1mt MDS-RS patient. This patient displayed active competition of two clones propagated by SF3B1N626D and SF3B1K666N mutations and was followed in the clinic over the course of 12 years, providing a unique opportunity to investigate clonal dynamics in MDS-RS (Figure 1). Methods: We performed whole-genome sequencing (WGS) of HSPC-generated colony-forming units (CFU), high-throughput 10X single-cell RNA sequencing (RNAseq) of CD34+ HSPCs and combined single-cell DNA + RNAseq (TargetSeq) of FACS-purified HSPC compartments to molecularly characterize the two distinct SF3B1mt clones in bone marrow samples acquired before, during and after the points of clonal inversion. Results: Genotype tracking displayed an initial rapid expansion of the N626D clone over approximately 2 years, followed by spontaneous expansion of the K666N clone. SF3B1K666N eventually dominated the bone marrow, driving a complete inversion of clonal prevalence. This active competition was underlined only by stable subclinical anemia (median 12.5 g/L, range 12.0 - 13.2 g/L) and a continued decrease in ring sideroblast frequency over time (from 42% to 8% RS), both in the absence of any treatment. The acquisition of either SF3B1 mutation was found to precede the diagnosis of MDS-RS by at least 20 years, and either mutation was associated with an increased mutational rate. Mirroring previous studies, we identified a deleterious alternative splicing profile common to both SF3B1 genotypes in HSPC subsets; however, this was accompanied by unique mis-splicing profiles specific to each mutation which potentially drive their differential expansion ability. Summary/Conclusion: We identified mutation-specific splicing profiles and intricate patterns of tumor suppressor gene expression as potential compound factors to the varied clonal fitness of SF3B1 mutations. This unique patient enabled the identification and tracking of mechanisms underlying long-term clonal expansion and competition, which we aim to verify in further work.Keywords: Hematopoiesis, Myelodysplastic syndrome, RNA-seq, Myelodysplasia
P441: CLINICAL AND MOLECULAR CHARACTERISTICS OF AML PATIENTS WITH AN EXCEPTIONAL RESPONSE TO IVOSIDENIB
Authors: Justin M. Watts, Prapti A Patel, Sung Choe, Xiaofei Bai, Dylan M Marchione, Eytan Stein
Journal: HemaSphere (2023)

Background: Ivosidenib (IVO) was approved based on a CR/CRh rate of 31.8% in IDH1-mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months. Aims: The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 months. Results: Of 179 patients who received IVO 500mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 patients (35.1%) had a DOR >12 months. After excluding 7 patients who went to HSCT, 13 patients (22.8% of responders, 7.3% of cohort) had DOR >12 months (exceptional response) and 8 of these patients (14% of responders, 4.5% of cohort) had DOR >24 months. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 months. Median OS was not reached; estimated OS at 48 months was 67.1%. Median EFS was 44.4 months. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient decision (n=3). Three patients remain on treatment. All patients who relapsed had DOR between 1-2 years; none of the 8 patients with DOR >2 years relapsed. Among the 13 exceptional responders, median age was 67 (range 58-77), 54% of patients were male, 77% had ECOG 0-1 (23% ECOG 2), and 69% of patients had de novo AML (31% secondary). Median number of prior therapies was 1 (range 1-3). Eight (62%) patients had untreated relapse and 5 (39%) had primary refractory disease; 3 (23%) had prior HSCT. The median bone marrow blast percentage was 35% (range 5-90%). The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five patients (39%) had a splicing factor mutation. No patients had FLT3 or RTK pathway mutations other than JAK2. Only 1 patient with NPM1 had an exceptional response, and 1 patient had TP53 (VAF 3.6%). Six patients (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most patients had intermediate-risk cytogenetics (10 patients, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven (85%) patients had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8/13 patients (61.5%). Summary/Conclusion: A subset of patients with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders), and no patients in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response.Keywords: relapsed/refractory, Ivosidenib, Acute myeloid leukemia